Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

Li, Yan; Abdourahman, Aicha; Tamm, Joseph A.; Pehrson, Alan L.; Sanchéz, Connie; Gulinello, Maria

doi:10.1016/j.pbb.2015.05.013

Cited by 70 publications

(65 citation statements)

References 140 publications

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“…Generally, locomotion decreases with advancing age in humans [84]; however, animal studies have reported inconsistent results regarding the age-related changes in the locomotor behavior. For example, some studies have demonstrated age-related decline in locomotor activity in WT mice [85–87], while others have reported no significant age-related changes in locomotion [88, 89]. We found a significant increase in locomotion in the control LFD mice at 32 weeks compared to the 21 week time point, but our mice were not aged as the mice in [85–87].…”

Section: Discussioncontrasting

confidence: 56%

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake

Krishna

Lin

Serre

et al. 2016

Physiology & Behavior

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High-fat diet (HFD) induced obesity is associated not only with metabolic dysregulation, e.g., impaired glucose homeostasis and insulin sensitivity, but also with neurological dysfunction manifested with aberrant behavior and/or neurotransmitter imbalance. Most studies have examined HFD's effects predominantly in male subjects, either in the periphery or on the brain, in isolation and after a finite feeding period. In this study, we evaluated the time-course of selected metabolic, behavioral, and neurochemical effects of HFD intake in parallel and at multiple time points in female (C57BL/6) mice. Peripheral effects were evaluated at three feeding intervals (short: 5–6 weeks, long: 20–22 weeks, and prolonged: 33–36 weeks). Central effects were evaluated only after long and prolonged feeding durations; we have previously reported those effects after the short (5–6 weeks) feeding duration) [1]. Ongoing HFD feeding resulted in an obese phenotype characterized by increased visceral adiposity and, after prolonged HFD intake, an increase in liver and kidney weights. Peripherally, 5 weeks of HFD intake was sufficient to impair glucose tolerance significantly, with the deleterious effects of HFD being greater with prolonged intake. Similarly, 5 weeks of HFD consumption was sufficient to impair insulin sensitivity. However, sensitivity to insulin after prolonged HFD intake was not different between control, low-fat diet (LFD) and HFD-fed mice, most likely due to age-dependent decrease in insulin sensitivity in the LFD-fed mice. HFD intake also induced bi-phasic hepatic inflammation and it increased gut permeability. Behaviorally, prolonged intake of HFD caused mice to be hypoactive and bury fewer marbles in a marble burying task; the latter was associated with significantly impaired hippocampal serotonin homeostasis. Cognitive (short-term recognition memory) function of mice was unaffected by chronic HFD feeding. Considering our prior findings of short-term (5–6 weeks) HFD-induced central (hyperactivity/anxiety and altered ventral hippocampal neurochemistry) effects and our current results, it seems that in female mice some metabolic/inflammatory dysregulations caused by HFD, such as gut permeability, appear early and persist, whereas others, such as glucose intolerance, are exaggerated with continuous HFD feeding; behaviorally, prolonged HFD consumption mainly affects locomotor activity and anxiety-like responses, likely due to the advanced obesity phenotype; neurochemically, the serotonergic system appears to be most sensitive to continued HFD feeding.

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Section: Discussioncontrasting

confidence: 56%

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake

Krishna

Lin

Serre

et al. 2016

Physiology & Behavior

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“…Evidence from clinical trials suggests that vortioxetine ameliorates some aspects of MDD-associated cognitive impairment, for example, speed of processing, executive function, and memory. This is supported by evidence from a number of preclinical experiments (du Jardin et al, 2014; Jensen et al, 2014; Wallace et al, 2014; Li et al, 2015). Much of the recent research efforts from our laboratory have been aimed at understanding the biologic mechanism by which vortioxetine exerts these beneficial effects on cognitive function.…”

Section: Introductionmentioning

confidence: 70%

“…Therefore, if vortioxetine’s cholinergic mechanisms are mediated via effects at either of these targets, then our study may have underestimated the impact of the cholinergic system in clinical populations. Additionally, the behavioral data are limited to assessments of social recognition memory, object recognition memory, and attention; thus, caution should be exercised when extrapolating to other cognitive domains that are improved by vortioxetine in the clinic, for example, processing speed and executive function (du Jardin et al, 2014; Jensen et al, 2014; Wallace et al, 2014; Li et al, 2015). Moreover, although the neurochemical data presented in this work may suggest that vortioxetine has limited effects on cholinergic neurotransmission, this should be viewed with caution until empirical evaluations of other cognitive domains have been evaluated.…”

Section: Discussionmentioning

confidence: 99%

Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats

Pehrson

Hillhouse

Haddjeri

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission. The current work sought to evaluate the ACh hypothesis by examining vortioxetine’s ability to reverse scopolamine-induced impairments in rodent tests of memory and attention. Additionally, vortioxetine’s effects on hippocampal extracellular ACh levels were examined alongside studies of vortioxetine’s pharmacokinetic profile. We found that acute vortioxetine reversed scopolamine-induced impairments in social and object recognition memory, but did not alter scopolamine-induced impairments in attention. Acute vortioxetine also induced a modest and short-lived increase in hippocampal ACh levels. However, this short-term effect is at variance with vortioxetine’s moderately long brain half life (5.1 hours). Interestingly, subchronic vortioxetine treatment failed to reverse scopolamine-induced social recognition memory deficits and had no effects on basal hippocampal ACh levels. These data suggest that vortioxetine has some effects on memory that could be mediated through cholinergic neurotransmission, however these effects are modest and only seen under acute dosing conditions. These limitations may argue against cholinergic mechanisms being the primary mediator of vortioxetine′s cognitive effects, which are observed under chronic dosing conditions in patients with MDD.

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“…In contrast, citalopram (up to 10 mg/kg) given sub-acutely to middle-aged OVX rats had no effect in the FST (Vega Rivera et al, 2016), although it did produce an AD-like effect in middle-aged OVX rats that had been subjected to chronic mild stress (Romano-Torres and Fernandez-Guasti, 2010). Chronic treatment with fluoxetine had no effect in middle-aged female mice (Li et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Comparison of the Antidepressant-Like Effects of Estradiol and That of Selective Serotonin Reuptake Inhibitors in Middle-Aged Ovariectomized Rats

Benmansour

Arroyo

Frazer

2016

Front. Aging Neurosci.

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This study investigated the effect of age and that of the post-ovariectomy (OVX) time interval on the antidepressant (AD)-like effects of estradiol (E2) and selective serotonin reuptake inhibitors (SSRIs) in middle-aged (10 month) OVX rats (10m-OVX). Acute or chronic effects of these treatments in 10m-OVX were compared with those (1) in young adult (4-month) OVX rats (4m-OVX) or with older (14-month) OVX rats (14m-OVX), at a short time: 2 weeks post-OVX (+2w) and (2) in 10m-OVX rats after a longer times: 4 or 8 months post-OVX (+4m or +8m). Using in vivo chronoamperometry in the CA3 region of the hippocampus, E2 at 20 pmol, a dose shown previously to inhibit the serotonin transporter (SERT) in 4m-OVX, had no effect in 10m-OVX+2w. A higher dose of E2 (40 pmol) increased T80 value, a measure of serotonin or 5-hydroxytryptamine (5-HT) clearance, and also blocked the ability of fluvoxamine to increase T80. By contrast, estradiol had no effects on SERT function in 10m-OVX+4m, even at a higher dose than 40 pmol. Fluvoxamine slowed 5-HT clearance in 10m-OVX at +2w, +4m and +8m post-OVX as it did in the 4m-OVX. Using the forced swim test, 2 weeks treatment with E2 (5 μg/day), a dose shown previously to induce AD-like effects in 4m-OVX, had no effect in 10m-OVX+2w. However, a higher dose (10 μg/day) of E2 induced an AD-like effect as demonstrated by significantly increased swimming behavior and decreased immobility. This effect was not seen in 10m-OVX+4m. By contrast, significant AD-like effects were obtained in 14m-OVX+2w, thereby demonstrating that the lack of an AD effect of E2 is due to the 4-month hormone withdrawal and not to an age effect. After 2 weeks treatment with the SSRI sertraline, similar AD-like effects were obtained in 10m-OVX tested at +2w, +4m or +8m post-OVX as those found in 4m-OVX. Thus, the potency of estradiol to produce effects consistent with inhibition of the SERT was not only decreased in older rats but its effects were markedly diminished the longer hormonal depletion occurred. By contrast, the ability of SSRIs to inhibit the SERT was not affected either by age or the length of hormonal depletion.

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Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

Cited by 70 publications

References 140 publications

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake

Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats

Comparison of the Antidepressant-Like Effects of Estradiol and That of Selective Serotonin Reuptake Inhibitors in Middle-Aged Ovariectomized Rats

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